基于光热化学联合治疗以Click化学逐级构建的肿瘤微环境响应式靶向纳米给药系统及其机制研究

At present, traditional chemotherapy, radiotherapy and surgery methods can exhibit better treatment of in situ tumors, but with inevitable sever toxicity and trauma. Therefore, novel tumor targeting methods-combined treatment is an urgent desire. For superficial malignant tumor, photothermal therapy and chemotherapy-combined therapeutic drug delivery system was constructed in response to the tumor microenvironment stimulus, which would employ the cell ablation for photothermal conversion and cell active targeting via matrix barriers for chemical drugs. Based on the dual targting effects of the outerlayer, which are induced by pazopanib targeting modification to the cancer tissue and iRGD-mediated matrix penetration delivery, multi approaches-combined treatment for breast cancer is achieved as follows while breaking through the layers of barriers: polydopamine killing cells by heat converted from light, pazopanib inhibiting angiogenesis and tumor cell migration, epirubicin electrostatically absorbed in outer lipid layer damaging DNA/RNA, to break through the layers of barriers to multi pronged treatment of cancer. The system is characterized by realizing the photothermal therapy particles combined with first-line chemotherapy, being sensitive to the tumor microenvironment, step by step assembling by click reaction/releasing. By exploring the transmission rules of combined drug loading technology, targeting absorption/stepwisely drug release, and synergy and attenuation. The systematic research mode of the gradually constructed combined therapeutic nanocarrier to achieve multi-channel antitumor efficacy could be provided by our work, which would also further improve the pharmaceutical theory for antitumor targeting drug delivery system with combined therapy.

目前传统化疗、放疗和手术等手段虽可较好治疗原位肿瘤，但毒副作用大、创伤严重，因此迫切需要新型肿瘤靶向多手段联合治疗。针对浅表性恶性肿瘤，本课题从光热转换致细胞消融、药物跨越基质屏障主动靶向出发，响应肿瘤微环境刺激，以Click反应链接构建新型光热化学联合治疗给药系统，经外层修饰帕唑帕尼靶向癌组织和iRGD介导穿透递送屏障的双重靶向作用，利用聚多巴胺内核光转换热能杀灭细胞、帕唑帕尼抑制血管增生与肿瘤迁移、外层脂质吸附的表柔比星造成DNA/RNA损伤，达到突破层层障碍多管齐下治疗癌症的目的。该系统具有实现光热治疗颗粒结合一线化疗药物、肿瘤微环境敏感、Click反应逐级组装/释放等特点，通过探求联合载药技术、靶向吸收/逐级释药过程、增效减毒之间传变规律，为逐级构建联合治疗纳米载体以实现多途径抑瘤提供系统性的研究模式，进一步完善抗肿瘤联合治疗靶向给药系统的制剂学理论。

目前传统化疗、放疗和手术等手段虽可较好治疗原位肿瘤，但毒副作用大、创伤严重，因此迫切需要新型肿瘤靶向多手段联合治疗。针对浅表性恶性肿瘤，本课题从光热转换致细胞消融、药物跨越基质屏障主动靶向出发，响应肿瘤微环境刺激，构建新型双重修饰荷载表柔比星的聚多巴胺光热化学联合治疗给药系统（E/PCF-NPs），成球形或类球形，分散性良好，粒径在106.7nm，EPI包封率为99.7%，4℃条件下稳定性良好，体外缓慢释放，光照后E/PCF-NPs可使细胞活力下降85%。药动学结果显示E/PCF-NPs体内生物半衰期延长，瘤内分布增加。双靶向修饰利于递送药物穿过肿瘤屏障，利用聚多巴胺内核光转换热能杀灭细胞、外层脂质吸附的表柔比星造成DNA/RNA损伤，最终使E/PCF-NPs能有效清除肿瘤，且未见毒性。该系统实现光热治疗颗粒结合一线化疗药物，为构建联合治疗纳米载体实现双重抑瘤提供系统性的研究模式，进一步完善抗肿瘤联合治疗靶向给药系统的制剂学理论。

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